Using three models of acute lung injury in rats (following intrapulmonary deposition of IgG or IgA immune complexes, or after systemic activation of complement), we will assess the roles of L-P-,E-selectins in these models of lung injury, employing Ig-selectin chimeras as well as blocking antibodies. Secondly, employing newly developed methods for the measurements of ICAM-1, and P- and E-selectins, we will quantitatively assess in vivo the upregulation of these adhesion molecules in the three models of lung injury. We will then determine the extent to which complement and cytokines (TNFalpha, IL-1) are required for the in vivo upregulation of the endothelial adhesion molecules. Thirdly, we will extend preliminary studies that suggest potent regulatory effect of IL-4 and IL-10 on inflammatory injury following intrapulmonary deposition of IgG or IgA immune complexes. We will assess the effects of IL-4 and IL- 10 on bronchoalveolar lavage (BAL) fluids for content of TNFalpha, IL-1 and MCP-1 in the models of immune complex-induced lung injury. The effects of IL-4 and IL-10 on in vivo upregulation of ICAM-1 and E- selectin will also be assessed. In parallel, we will determine in vitro the effects of IL-4 and IL-10 on transcriptional upregulation of endothelial ICAM-1, E-selectin, TNFalpha, IL-1 and MCP-1 and alveolar macrophage expression of the latter three cytokines. Fourthly, rat VCAM- 1 will be expressed in the baculovirus system and anti-VCAM-1 antibodies will be obtained and used in vivo in the immune complex models to assess the role of VCAM-1. Fifthly, we will pursue in vitro studies with monolayers of Type I rat alveolar epithelial cells in order to determine Beta 2 integrin requirements for adhesive interactions with rat alveolar macrophages and how these adhesive interactions affect production of O2 and TNFalpha in the macrophages. These studies should provide substantial, additional information regarding the role of adhesion molecules and cytokines in lung injury. Finally, as animals are available, employing transgenic mice with intrapulmonary expression of C5a or the IL-8/gro homologue, KC, or using mice with C5a or KC receptor "knockout", we will determine the effects of these manipulations on lung morphology and on complement dependent lung inflammatory reactions (using in mice the models of lung injury referred to above).